1. Fields of the Invention
The present invention relates to a quinic acid derivative, particularly to a cynarin-analogous quinic acid derivative which binds to CD28, preparation process of the same from a quinic acid and pharmaceutical uses via suppressing T-cell activation thereof.
2. Descriptions of Related Art
T-cells play a pivotal role in the initiation and regulation of immune responses to antigens. The activation of T-cells is tightly controlled by many positive and negative regulatory processes to prevent pathologically over-active or under-active immune responses. Optimal T-cell activation requires both signal 1 and signal 2 pathways while T-cells are stimulated by specific external stimuli. Antigen-presenting cells (APCs) such as dendritic cells express major histocompatibility complex (MHC) molecules on their cell surfaces and present antigen fragments with the MHC molecules. The signal 1 pathway is initiated by a binding interaction between the T-cell receptor (TCR) of T-cells and the antigen-MHC complex of APCs. The signal 2 is induced by a binding between a co-stimulatory molecule such as CD80 (also known as B7-1) or CD86 (also known as B7-2) of APCs and CD28 of T-cells, providing a co-stimulatory pathway. TCR engagement in the absence of the signal 2 leads to T-cell anergy which is a hyporesponsive state of T-cells.
The complete immune activation of T-cells is not desirable in response to self-antigens or allergens. The over-activations of T-cells against self-antigens or allergens cause autoimmune diseases or allergic conditions. Thus, declining the signal 2 pathway to promote T-cell anergy represents a strategy for the treatment of an autoimmune disease or an allergy. Because of the overlapping among intercellular signal transduction pathways, interfering signal pathways inside cell may cause a sever side effect (e.g., both signal 1 and signal 2 are simultaneously blocked). Thus, blocking signal pathways (e.g., either signal 1 or signal 2 can only be blocked) from outside provides a milder way to suppress signal transduction. For example, a non-mitogenic anti-CD28 antibody can be considered as a T-cell blocker to block the signal 2 pathway outside the T-cell. However, due to the fragile nature and the poor stability of antibodies, using them as drugs has many drawbacks. Acid and luminal proteases in the gastrointestinal tract limit oral availability of antibodies, and antibodies loss their 3D structures and functions easily. Otherwise, immune responses may be induced by antibody drugs and therefore lower the therapeutic utility of antibody drugs.
Using small compounds which mimic metabolites as drugs to block target pathways can overcome the drawbacks described above. To develop an ideal T-cell blocker, the inventor establishes a screening method named “after flowing through immobilized receptor (AFTIR) method” which refers to Taiwanese patent publication no. 1355493 and uses it to isolate a targeting component which specifically binds to CD28 from western purple coneflower (Echinacea purpurea) extracts. The targeting component is identified as cynarin, which having the formula as shown in FIG. 1. Due to the cytotoxicity of cynarin, the inventor delivers a cynarin analogue which is effective to block CD28 but less cytotoxic than cynarin. The inventor finds out that the key blocking factor (KBF) of cynarin binding to CD28 is a quinic acid-like section by molecular dynamic simulating 3D structures of cynarin and CD28. Thus, the inventor derives a cynarin-analogous quinic acid derivative with modifications for attenuating the cytotoxicity.
Accordingly, the present invention provides a cynarin-analogous quinic acid derivative, process for preparation the same from a quinic acid and pharmaceutical uses via suppressing CD28-dependent T-cell activation thereof. According to the present invention, the drawbacks according to the prior art such as anti-CD28 antibodies or cynarin as described above can be improved; the oral stability can be increased; and the cytotoxicity can be attenuated.